| Autor: |
Baertling, Fabian, Al‐Murshedi, Fathiya, Sánchez‐Caballero, Laura, Al‐Senaidi, Khalfan, Joshi, Niranjan P, Venselaar, Hanka, den Brand, Mariël AM, Nijtmans, Leo GJ, Rodenburg, Richard JT |
| Zdroj: |
Human Mutation; Jun2017, Vol. 38 Issue 6, p692-703, 12p |
| Abstrakt: |
COX5A is a nuclear-encoded subunit of mitochondrial respiratory chain complex IV (cytochrome c oxidase). We present patients with a homozygous pathogenic variant in the COX5A gene. Clinical details of two affected siblings suffering from early-onset pulmonary arterial hypertension, lactic acidemia, failure to thrive, and isolated complex IV deficiency are presented. We show that the variant lies within the evolutionarily conserved COX5A/COX4 interface domain, suggesting that it alters the interaction between these two subunits during complex IV biogenesis. In patient skin fibroblasts, the enzymatic activity and protein levels of complex IV and several of its subunits are reduced. Lentiviral complementation rescues complex IV deficiency. The monomeric COX1 assembly intermediate accumulates demonstrating a function of COX5A in complex IV biogenesis. A potential therapeutic lead is demonstrated by showing that copper supplementation leads to partial rescue of complex IV deficiency in patient fibroblasts. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
|
Plný text